PROJECT SUMMARY Coronary microvascular disease (CMVD), or disease of the coronary pre-arterioles, arterioles, and capillaries, has become an increasingly well-recognized cardiac pathology, which carries a high burden of morbidity, healthcare costs, and increased mortality. CMVD exists in isolation and also exacerbates other cardiac disease such as coronary artery disease (CAD) and cardiomyopathies. In addition, the pathophysiology of CMVD also has implications for heart failure with preserved ejection fraction (HFpEF) and coronary collateral formation. The Hypoxia-Inducible Factor 1a (HIF) pathway is activated in response to hypoxia and has been studied in the context of coronary microvasculature and cardiac perfusion. Signaling through the HIF pathway promotes angiogenesis and may improve microvascular structure, however, the HIF pathway is known to have deleterious metabolic effects on cardiomyocytes. Uncoupling the beneficial angiogenic and deleterious metabolic effects of the HIF pathways would therefore be highly beneficial. Evidence that FOG2, a transcriptional co-activator of GATA4, is a key regulator of coronary development and the maintenance of coronary microvasculature into adulthood, have led to the novel hypothesis that FOG2 is a critical regulator in the HIF pathway and that FOG2 can mediate HIF-induced coronary angiogenesis without deleterious effects on cardiac metabolism. I have developed a translational framework consisting of 1) a mouse model of CMVD and 2) functional imaging of the mouse coronary microvasculature to help investigate this hypothesis. Three interrelated Specific Aims will address the hypothesis: 1) Characterize HIF-induced angiogenesis and metabolic changes in cardiomyocytes and determine whether FOG2 mediates HIF induction of angiogenic and metabolic pathways in cardiomyocyte cell culture; 2) Delineate the role of HIF and FOG2 pathways in CMVD and determine whether FOG2 mediates HIF induction of coronary angiogenesis without affecting cardiac metabolism in mice; and 3) Define the role of the HIF and FOG2 pathways in CMVD in humans. The experiments in this innovative proposal will also have direct application toward the development of novel therapies for CMVD. In addition, the research proposal is supported in an integrated manner through exceptional mentorship, a research advisory committee filled with relevant expertise, and unequivocal divisional and institutional commitment. Finally, this K08 award will serve as a basis for the achievement of my ultimate career goal to become an independent physician-scientist at a major academic medical center.